Extended-Release 7-Day Injectable Buprenorphine for Patients With Minimal to Mild Opioid Withdrawal

Key Points Question Is a 7-day preparation of extended-release buprenorphine feasible for patients with minimal to mild opioid withdrawal? Findings In this nonrandomized trial of 100 adult patients with opioid use disorder presenting with minimal to mild Clinical Opiate Withdrawal Scale scores (0-7), 7% of patients experienced precipitated withdrawal within 4 hours of 7-day extended-release buprenorphine administration, which included 3% with higher scores (4-7) and 14% with lower scores (0-3). Meaning Results of this study suggest that 7-day extended-release buprenorphine may be feasible in patients with opioid use disorder presenting with minimal to mild Clinical Opiate Withdrawal Scale scores (4-7), which could increase the number of patients receiving buprenorphine induction.


Introduction
Buprenorphine treatment of opioid use disorder (OUD) is effective in engaging patients in addiction treatment and reducing illicit opioid use and overdose mortality [1][2][3] and is cost-effective in multiple health care settings. 4,5Despite an increasing and relentless opioid overdose epidemic, 6 buprenorphine is underused 7 for a variety of clinical and logistical reasons. 8,9Barriers may include a patient's lack of insurance, prior authorization requirements, limited pharmacy availability, and transportation.Furthermore, stigma, 10,11 along with clinician concerns regarding prescribing (eg, misuse and diversion) and the ability to arrange an adequate, timely follow-up, also limits adoption. 8spite new legislation that removed federal regulatory barriers, buprenorphine prescribing has not significantly increased. 12,13Among emergency department (ED) patients with OUD who accept treatment, as many as 50% are not in sufficient opioid withdrawal at the time of their ED visit to administer buprenorphine without risk of precipitating withdrawal. 1 To date, there is little evidence for rapid strategies to initiate buprenorphine without the prerequisite withdrawal. 14Thus, patients are often instructed to initiate buprenorphine on their own after a brief education 15 or are discharged without medication treatment, leaving them at risk for overdose. 16new 7-day injectable formulation of extended-release buprenorphine, known as CAM2038 (Braeburn), 17 offers a novel method to initiate buprenorphine that does not require stabilization on sublingual buprenorphine and therefore provides an opportunity to surmount many of the barriers associated with the sublingual formulation.A 7-day single injection avoids unnecessary delays to full induction and addresses the often-fragmented and barrier-laden health care system that may thwart rapid access to follow-up care.Our group's clinical experience with this 7-day injectable formulation of extended-release buprenorphine has been previously described.18 The slower rate of rise in plasma buprenorphine concentration of extended-release buprenorphine, reaching 1.6 ng/mL in 4 hours compared with 5.6 ng/mL in sublingual dosing, 19 potentially permits buprenorphine initiation in patients with minimal to mild withdrawal, as measured by the Clinical Opioid Withdrawal Scale (COWS).20 This could allow more patients to benefit from buprenorphine induction with 7 days of ensured medication delivery and time to obtain outpatient follow-up. Ths, we evaluated the feasibility, including acceptability, tolerability, and safety, of extended-release buprenorphine in patients with untreated OUD exhibiting minimal to mild withdrawal, defined as COWS scores ranging from 0 to 7 (in which higher scores indicate increasing withdrawal), in a multicenter single-arm prospective study conducted under a US Food and Drug Administration investigational new drug application.

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Extended-Release 7-Day Injectable Buprenorphine for Mild Opioid Withdrawal

Methods
This nonrandomized trial, the Emergency Department-Initiated Buprenorphine Validation Network Trial, was approved by a single investigational review board, the WCG Institutional Review Board.
This study followed the Transparent Reporting of Evaluations With Nonrandomized Designs (TREND) reporting guideline. 21Written informed consent was obtained.

Setting and Participants
The study was conducted in 4 US urban teaching hospital EDs in the Northeast, mid-Atlantic, and Pacific geographic areas by emergency physician investigators (G.D., A.A.H., J.P., K.H., E.A.S., and E.A.) experienced with initiating buprenorphine.Patients 18 years or older were screened for opioid use using a tool embedded in a health questionnaire during select times.Patients were eligible if they met Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for moderate to severe OUD 22 with a urine point-of-care toxicology test positive for opioids, had a COWS score less than 8 (denoting minimal to mild withdrawal), and were able to speak English.Patients were excluded if their urine was positive for methadone or if they presented after an opioid overdose, were pregnant, were actively suicidal, required opioids for pain, or were enrolled in OUD treatment receiving medications in the past 7 days.Patients with a positive fentanyl test only were enrolled based on clinician assessment, as rapid fentanyl testing is not approved for clinical use.Using methods previously described as the ancillary study in a larger parallel trial investigating sublingual vs extended-release buprenorphine, 23 75 patients with COWS scores of 0 to 7 (13 with COWS scores of 0-3 and 62 with COWS scores of 4-7) were enrolled from July 13, 2020, to April 4, 2021.As 83% of the patients enrolled had a COWS score between 4 and 7, the decision was made to continue enrolling an additional 25 patients with COWS scores of 0 to 3 from April 5, 2021, to May 25, 2023.
Compensation included gift cards provided for enrollment ($100), 1-to 7-day telephone assessments ($50), and the 7-day follow-up ($50), with a maximum of $200.Race and ethnicity categories were ascertained by self-identification and included Asian; Black or African American; Hispanic or Latino; White; multiracial; and other (in which responses included ethnicity only: Hispanic, Latino, Mexican, or Puerto Rican), unknown, or declined to answer.

Intervention
Patients received a 24-mg dose of CAM2038, equivalent to 16 mg of buprenorphine daily.They remained in the ED for 4 hours after injection to observe for worsening or precipitated withdrawal.
Ancillary medications for specific symptoms were available per protocol.Patients were referred to community-based programs or clinicians for ongoing OUD treatment as usual for each site.

Primary Outcomes Measures
The primary outcomes assessing feasibility include the number of participants who (1) experienced a 5-point or greater increase in the COWS score within 4 hours of extended-release buprenorphine injection or (2) transitioned to moderate or greater withdrawal (defined as COWS scores of Ն13) within 4 hours of the extended-release buprenorphine injection or (3) experienced precipitated withdrawal within 1 hour of the extended-release buprenorphine injection.To adjudicate precipitated withdrawal, the medical records (COWS, urine toxicology results, time since last opioid use, route of administration, and ED course) of patients who experienced a 5-point or greater increase in COWS scores were reviewed by researchers (S.L.W. and M.R.L.) involved in the original CAM2038 phase 2 19 and phase 3 24 trials, who were not involved in the clinical care of study patients.We hypothesized that within 4 hours of injection, (1) fewer than 20% of patients would experience a 5-point or greater increase in COWS, (2) less than 10% would transition to moderate or greater withdrawal (a COWS score of Ն13), and (3) less than 10% of patients would experience precipitated withdrawal within 1 hour.

Assessments Index ED Visit
Baseline data were collected on demographics, other substance use, and overdose events.COWS scores were completed prior to extended-release buprenorphine injection and every 30 minutes after injection up to 4 hours.
The Numeric Pain Rating Scale 24 assessed the patient's degree of pain at the injection site, based on a total pain score of 10, in which 0 indicated no pain and 10 was the worst possible pain, immediately after injection and at 30 minutes and 4 hours after injection.A local tolerability scale 24 was assessed by the research associate 30 minutes after injection and after 4 hours regarding erythema and superficial swelling.Erythema was rated from none, mild (barely perceptible), moderate (well-defined erythema), or severe (from beet redness to a slight eschar formation).

Daily Text Qualtrics Assessments, Days 1 to 7
Qualtrics surveys using text messaging were conducted for 7 days.The assessments included items regarding craving (a visual analog scale to assess how much opioids were currently desired, ranging from 0 to 100, with higher scores indicating more craving) and use of nonprescribed opioids or other drugs in the past 24 hours (yes or no response).

Day-7 Assessments Conducted In Person and by Telephone
Injection-site assessment included self-report of the Numeric Pain Rating Scale; the presence of itching, discharge, and/or tenderness (yes or no); and erythema and/or swelling.A patient satisfaction scale evaluated the patient's overall experience with extended-release buprenorphine on a scale from 1 (completely ineffective) to 5 (completely effective).Seven questions evaluated the importance of characteristics with an injectable formulation including not requiring daily medication; preventing others from accessing medication; allowing travel without carrying medication; sparing regular visits to the pharmacy; preventing accidental exposure to children or pets; improving privacy; and helping to make sure medication doses were not missed.Questions were rated on a scale of 1 (not important) to 7 (extremely important).Opioid overdose events were reported for the 7 days after enrollment.Urine point-of-care toxicology testing was conducted on all patients who completed in-person day 7 assessments.
Engagement in OUD treatment was assessed by self-report as receiving treatment for OUD (yes or no).If the response was yes, the name and type of treatment (methadone, buprenorphine, naltrexone, short-term medically managed withdrawal, inpatient, outpatient counseling, virtual care, or other) were recorded.

Entire Study Period
Adverse events included any episode of precipitated withdrawal and any other symptoms that were reported during the 7-day study period.Serious adverse events were all-cause hospitalizations or deaths during the 7-day study period.

Statistical Analysis
An initial sample size was justified on the basis of acceptable exact 95% CI widths for the primary feasibility outcomes.If the proportion meeting a primary outcome event definition was 1%, the 95% CI would have a width (ie, difference between upper and lower 95% CI bounds) of 6.64%.Point estimates of 5%, 10%, and 20% for the primary outcomes would have widths of 11%, 15%, and 19%, respectively.Given the low number of patients with COWS scores less than 4 in the initial patients, the Data and Safety Monitoring Board recommended recruitment of additional patients exclusively with COWS scores of less than 4.

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Extended-Release 7-Day Injectable Buprenorphine for Mild Opioid Withdrawal Primary outcomes were summarized with percentages of patients experiencing events and associated exact 95% CIs based on the Clopper-Pearson method. 25We conducted analyses with stratification by a baseline COWS score and the presence or absence of fentanyl in patients' urine on urine toxicology testing given reported challenges with buprenorphine initiation in patients using fentanyl. 26Changes in COWS scores from baseline are presented by each patient over 4 hours after injection.Pain scores and craving are summarized using mean (SD), and treatment engagement, satisfaction, injection-site symptoms, and overdose events are summarized using frequencies (percentages).
Events based on COWS scores required a baseline value and 2 postbaseline values with at least 1 in the last hour of the 4-hour observation window.Patients without sufficient data were determined as having the event according to the planned worst-case scenario (ie, precipitated withdrawal) analysis.A 2-sided P < .05significance level was used.Analyses were conducted using SAS, version 9.4 (SAS Institute Inc).

Primary Outcomes
A total of 635 patients were evaluated for eligibility.Of these, 533 were ineligible, and 2 met eligibility criteria but were not enrolled, leaving our sample size of 100 (Figure 1), which included 75 patients in the initial sample size and 25 patients recruited exclusively with COWS scores of less than 4. Seven patients did not complete the 7-day follow-up assessments.However, 3 of these 7 patients responded to 1 or more daily assessments.Table 1 describes the demographic and substance use   One patient with a screening COWS score of 0 was admitted to a behavioral health unit prior to completing the observation period and returned with precipitated withdrawal.Another patient left prior to completing the observation period but called the study team at 4 hours and denied any withdrawal symptoms.Few patients, excluding those with precipitated withdrawal, received ancillary medications (eg, antiemetics, acetaminophen, and ibuprofen) (eTable 3 in Supplement 2).
a In this trial, scores range from 0 to 7, with higher scores indicating increasing withdrawal.
b Calculated using the exact Clopper-Pearson method. 25Includes COWS scores of 13 or greater.
d Adjudicated by an expert panel (M.R.L. and S.L.W.).
e One participant had a missing COWS score at baseline and is categorized using their screening value of 0.

Daily Assessments for Craving Severity and Illicit Drug Use
Between 72 and 88 of all patients reported an assessment at any given day, and 54 assessed their opioid use and craving on all 7 days.Table 3 illustrates the visual analog scale daily craving data and the number of respondents who reported any use of opioids in the past 24 hours.Between 29 (33%) and 31 (43%) respondents on any given day reported 0 cravings, and between 59 (78%) and 75 (85%) reported no use of opioids on any given day; 57 (60%) reported no days of opioid use.The risk of opioid use was higher for those with cravings greater than 0.

Injection-Site Assessment at 7 Days
Results for injection-site assessment at 7 days were available for 93 patients.Sixteen (17%) experienced at least 1 symptom at the injection site.Of those, 11 reported tenderness and 7 pain.The severity of the pain (10 maximum) was rated 0 to 3 by 6 patients and 8 to 10 by 1 patient.Other symptoms included redness (2 patients), swelling (2 patients), and itching (1 patient).buprenorphine; none received methadone or naltrexone.Three patients were in short-term medically managed withdrawal programs, and 3 were in an inpatient setting.Three patients reported receiving outpatient counseling, and 2 reported receiving virtual care.

Discussion
This nonrandomized trial is the first study, to our knowledge, to report the feasibility, including acceptability, tolerability, and safety, of a 7-day injectable extended-release buprenorphine formulation in patients with minimal to mild opioid withdrawal.The opportunity to initiate buprenorphine in patients without having to first experience prolonged withdrawal has many clear benefits and could substantially increase the number of patients with OUD able to initiate buprenorphine upon ED presentation.This finding may have a significant public health impact in light of the continued increase in opioid deaths in 2023 driven primarily from fentanyl 6 and the heightened risk of overdose death without medication treatment. 16Our findings should provide a valuable, new option for clinicians reticent to offer buprenorphine in patients using fentanyl.The overall incidence of precipitated withdrawal in the group with COWS scores of 4 to 7 was low (only 2 of 63 precipitated withdrawal patients) compared with 5 of 37 in the group with COWS scores of 0 to 3. Additional research is needed to clearly delineate the association between COWS scores and tolerance of buprenorphine initiation, particularly at the very low range.This is consistent with our group's recent publication of a study of 1200 patients in a clinical trial receiving either extendedrelease buprenorphine (COWS score of Ն4) or sublingual buprenorphine, which found that there were few patients with precipitated withdrawal (<1%), despite a high prevalence of fentanyl use. 28ven the low rate of precipitated withdrawal in COWS scores of 4 to 7 (3.2%),eligibility criteria to include patients with COWS scores of 4 to 7 were expanded in an ongoing randomized clinical trial, Emergency Department-Initiated BUP Validation, 23 comparing standard sublingual dosing with extended-release buprenorphine in rates of continued engagement in treatment by including those presenting with COWS scores of 4 to 7.
In addition to those experiencing precipitated withdrawal, some patients received ancillary medications, primarily clonidine, antiemetics, and nonopioid analgesics, all of which can be administered in most ambulatory settings.While the 7 patients with precipitated withdrawal used fentanyl, 63 patients using fentanyl underwent uneventful inductions.However, we caution against drawing any conclusions regarding the association of fentanyl on extended-release buprenorphine induction.
It is reassuring that extended-release buprenorphine was found to be acceptable and tolerable from our results.A large percentage (78%) of our study's patients (72 of 92) rated extendedrelease buprenorphine as effective in treating OUD (denoted by a 4 or 5 on the 5-point scale) and were overall very satisfied, noting that the extended-release buprenorphine injectable formulation did not require daily medication, regular pharmacy visits, or traveling with medications; promoted not missing a dose; improved privacy; and prevented accidental exposures.These are all important factors that may enhance retention in treatment and decrease stigma.Furthermore, overall pain and injection-site reactions were minimal.
Additionally, craving has been identified as an important factor in treatment outcomes, [29][30][31][32] and a recent systematic review found that buprenorphine reduces craving over time. 33Interestingly, in our study, between 33% and 43% of patients reported 0 cravings on daily assessments, which was associated with significant decreases in opioid use.Extended-release buprenorphine may also decrease the risk of overdose, as there were no reported incidences of overdoses in the 7 days after extended-release buprenorphine administration compared with the 6 patients who reported an overdose in the 7 days prior to treatment.
We found that 73% of patients engaged in OUD treatment within 7 days of the extendedrelease buprenorphine injection.An initial medication response has been shown to predict treatment outcomes with buprenorphine. 34Potentially, early and sustained administration of relatively high

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Extended-Release 7-Day Injectable Buprenorphine for Mild Opioid Withdrawal levels of buprenorphine that avoid any significant between-dose trough would assist with retention.
This percentage of engagement in treatment at 7 days was higher than ED implementation studies of sublingual buprenorphine that have reported 35.8% 35 and 48% 36,37 rates of engagement at 30 days post-ED-initiated buprenorphine.A shorter time assessment and the presence of wellestablished referral community partners may have contributed to this difference.However, given that this was a very vulnerable population, with 36% currently reporting unstable housing, this engagement rate is indeed noteworthy.

Limitations
This study has several limitations.The study was conducted in a small number of academic medical center EDs, using strict eligibility criteria, with ready access to injectable medication.There was no control condition.Despite strict eligibility criteria, there was some discretion on the part of the investigators when selecting patients with COWS scores of 0 to 3, which could have resulted in selection bias.As extended-release buprenorphine was provided by the study, the cost and insurance coverage did not present barriers to treatment.

Conclusions
This nonrandomized trial provides initial data on the feasibility of the use of a 7-day extended-release buprenorphine in adult patients with minimal to mild opioid withdrawal, finding this formulation to be acceptable, well-tolerated, and safe in those with COWS scores of 4 to 7.These findings address some of the oft-cited barriers to initiating buprenorphine and follow-up in the community and offer a much-needed option to increase buprenorphine treatment.Further research is needed to assess the criteria for use and risk benefit analyses for use in individuals with COWS scores of 0 to 3, denoting little to no evidence of withdrawal.

Figure 2
Figure 2 depicts the COWS scores over time.The COWS scores decreased for most patients.

Figure 2 .
Figure 2. Change in Clinical Opiate Withdrawal Scale (COWS) Scores Over Time

Table 1 .
by COWS scores of 0 to 3 and 4 to 7. Overall, patients had a mean (SD) age of 36.5(8.7)years,28 (28%) were female, and 72 (72%) were male.Among patients, 1 (1%) was Asian; 35 (35%) were Black or African American; 13 (13%) Hispanic or Latino; 51 (51%) White; 1 (1%) multiracial; and 9 (9%) other, unknown, or declined to answer.Forty-eight patients (48%) reported unstable housing in the past 12 months, with 36% currently living in unstable housing; 79 (79%) were insured by public insurance (ie, Medicaid); and 70 (70%) had a urine toxicology test positive for fentanyl.Of the additional 25 patients enrolled with COWS scores less than 4, 2 were enrolled with COWS scores of 0 (1 of whom was a screening COWS only and not repeated at the time of extended-release Patient Clinical Characteristics injection per protocol), 5 with COWS scores of 1, 8 with COWS scores of 2, and 9 with COWS scores of 3. One patient progressed to a COWS score of 4 by the time of medication administration.The primary outcomes by COWS scores and by the presence of fentanyl are presented in a 460 No opioid use in last 30 d 68 Required continued prescription opioids for pain condition 148 Did not meet DSM-5 criteria for OUD 102 No eligible COWS score 40 Currently enrolled in formal addiction treatment 11 Urine toxicology test not positive for opioids 34 Unwilling to follow study procedures 15 Medical or psychiatric condition that required hospitalization 10 Unable to provide reliable locator information 6 Pregnant at index ED visit 8 Unable to speak English 7 Index ED visit was due to opioid overdose 6 Actively suicidal or cognitively impaired 2 Treatment not during screening hours 4 Not 18 y of age 4 Urine toxicology test positive for methadone 2 Incarcerated or in police custody at time of index ED visit 1 Presented from an extended care facility 1 Unknown 2 Eligible but not enrolled COWS indicates Clinical Opiate Withdrawal Scale; DSM-5, Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition); ED, emergency department; OUD, opioid use disorder.aParticipants may not have met the inclusion criteria for more than 1 reason.characteristicsc Spent at least 1 night in a shelter for individuals experiencing homelessness; on the street or in a public place; in a hotel for individuals experiencing homelessness; in someone else's house or apartment; or in an emergency or a temporary, transitional, or halfway house.dPatients tested positive for 1 or more substances.buprenorphine

Table 2 )
, as did 70% of all enrolled patients (Table1).However, of note, 63 patients using fentanyl underwent uneventful inductions.The number, percentages, and 95% CIs are included for those with COWS scores in the 0 to 3 and 4 to 7 categories, with and without the presence of fentanyl, for all primary outcomes and precipitated withdrawal.Primary outcomes by COWS scores and enrollment site are presented in eTable 1 in Supplement 2. Primary outcomes by age, sex, race, and ethnicity are included in eTable 2 in Supplement 2.

Table 2 .
Summary of Primary Outcomes by Subgroups of COWS Scores and Presence of Fentanyl